Treatment of vascular occlusions using ultrasonic energy and microbubbles

ABSTRACT

In one embodiment of the present invention, a method of treating a vascular occlusion located at a treatment site within a patient&#39;s vasculature comprises positioning an ultrasound catheter at the treatment site. The method further comprises delivering a microbubble therapeutic compound from the ultrasound catheter to the vascular occlusion during a first treatment phase. The method further comprises pausing the delivery of the microbubble therapeutic compound and delivering ultrasonic energy from the ultrasound catheter to the vascular occlusion during a second treatment phase while the delivery of microbubble therapeutic compound remains paused.

PRIORITY APPLICATION

This application is a continuation of U.S. application Ser. No.11/046,208 filed Jan. 28, 2005, now U.S. Pat. No. 7,341,569, whichclaims the benefit of U.S. Provisional Application 60/540,491 filed Jan.30, 2004, which are hereby incorporated by reference herein in theirentirety.

FIELD OF THE INVENTION

The present invention relates generally to treatment of vascularocclusions, and more specifically to treatment of vascular occlusionswith ultrasonic energy and a therapeutic compound having microbubbles.

BACKGROUND OF THE INVENTION

Several medical applications use ultrasonic energy. For example, U.S.Pat. Nos. 4,821,740, 4,953,565 and 5,007,438 disclose the use ofultrasonic energy to enhance the effect of various therapeuticcompounds. An ultrasonic catheter can be used to deliver ultrasonicenergy and a therapeutic compound to a treatment site within a patient'sbody. Such an ultrasonic catheter typically includes an ultrasoundassembly configured to generate ultrasonic energy and a fluid deliverylumen for delivering the therapeutic compound to the treatment site.

As taught in U.S. Pat. No. 6,001,069, ultrasonic catheters can be usedto treat human blood vessels that have become partially or completelyoccluded by plaque, thrombi, emboli or other substances that reduce theblood carrying capacity of the vessel. To remove or reduce theocclusion, the ultrasonic catheter is used to deliver solutionscontaining therapeutic compounds directly to the occlusion site.Ultrasonic energy generated by the ultrasound assembly enhances theeffect of the therapeutic compounds. Such a device can be used in thetreatment of diseases such as peripheral arterial occlusion or deep veinthrombosis. In such applications, the ultrasonic energy enhancestreatment of the occlusion with therapeutic compounds such as urokinase,tissue plasminogen activator (“tPA”), recombinant tissue plasminogenactivator (“rtPA”) and the like. Further information on enhancing theeffect of a therapeutic compound using ultrasonic energy is provided inU.S. Pat. Nos. 5,318,014, 5,362,309, 5,474,531, 5,628,728, 6,001,069 and6,210,356.

SUMMARY OF THE INVENTION

Certain therapeutic compounds contain a plurality of microbubbleshaving, for example, a gas formed therein. The efficacy of a therapeuticcompound can be enhanced by the presence of the microbubbles containedtherein. The microbubbles act as a nucleus for cavitation, which canhelp promote the dissolution and removal of a vascular occlusion.Furthermore, the mechanical agitation caused motion of the microbubblescan be effective in mechanically breaking up clot material. Therefore,ultrasound catheter systems configured for use with amicrobubble-containing therapeutic compound have been developed.

In one embodiment of the present invention, a method of treating avascular occlusion located at a treatment site within a patient'svasculature comprises positioning an ultrasound catheter at thetreatment site. The method further comprises delivering a microbubbletherapeutic compound from the ultrasound catheter to the vascularocclusion during a first treatment phase. The method further comprisespausing the delivery of the microbubble therapeutic compound anddelivering ultrasonic energy from the ultrasound catheter to thevascular occlusion during a second treatment phase while the delivery ofmicrobubble therapeutic compound remains paused.

In one embodiment of the present invention, a method of treating avascular occlusion located at a treatment site within a patient'svasculature comprises passing an ultrasound catheter through thepatient's vasculature to the treatment site. The ultrasound catheterincludes at least one fluid delivery port. The method further comprisespositioning the ultrasound catheter at the treatment site such that theat least one fluid delivery port is positioned within the occlusion. Themethod further comprises infusing a microbubble therapeutic compoundfrom the ultrasound catheter into an internal portion of the occlusion.The method further comprises pausing delivery of the microbubbletherapeutic compound from the ultrasound catheter after a first quantityhas been infused into the occlusion. The method further comprisesdelivering ultrasonic energy from the ultrasound catheter into theinfused microbubble therapeutic compound. The method further comprisesrepositioning the ultrasound catheter at the treatment site. The methodfurther comprises infusing a second quantity of microbubble therapeuticcompound from the ultrasound catheter to the treatment site after theultrasonic energy is delivered to the treatment site.

In one embodiment of the present invention, an ultrasound cathetersystem comprises an elongate tubular body having an ultrasound radiatingmember and a fluid delivery lumen positioned therein. The system furthercomprises a fluid reservoir that is hydraulically coupled to a proximalportion of the fluid delivery lumen. The fluid delivery reservoircontains a microbubble therapeutic compound. The system furthercomprises an infusion pump configured to pump the microbubbletherapeutic compound from the fluid reservoir into the fluid deliverylumen. The system further comprises control circuitry configured to sendelectrical activation power to the infusion pump and to the ultrasoundradiating member. The control circuitry is configured such that theinfusion pump and the ultrasound radiating member are not activatedsimultaneously.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments of the vascular occlusion treatment system areillustrated in the accompanying drawings, which are for illustrativepurposes only. The drawings comprise the following figures, in whichlike numerals indicate like parts.

FIG. 1 is a schematic illustration of an ultrasonic catheter configuredfor insertion into large vessels of the human body.

FIG. 2 is a cross-sectional view of the ultrasonic catheter of FIG. 1taken along line 2-2.

FIG. 3 is a schematic illustration of an elongate inner core configuredto be positioned within the central lumen of the catheter illustrated inFIG. 2.

FIG. 4 is a cross-sectional view of the elongate inner core of FIG. 3taken along line 4-4.

FIG. 5 is a schematic wiring diagram illustrating an exemplary techniquefor electrically connecting five groups of ultrasound radiating membersto form an ultrasound assembly.

FIG. 6 is a schematic wiring diagram illustrating an exemplary techniquefor electrically connecting one of the groups of FIG. 5.

FIG. 7A is a schematic illustration of the ultrasound assembly of FIG. 5housed within the inner core of FIG. 4.

FIG. 7B is a cross-sectional view of the ultrasound assembly of FIG. 7Ataken along line 7B-7B.

FIG. 7C is a cross-sectional view of the ultrasound assembly of FIG. 7Ataken along line 7C-7C.

FIG. 7D is a side view of an ultrasound assembly center wire twistedinto a helical configuration.

FIG. 8 illustrates the energy delivery section of the inner core of FIG.4 positioned within the energy delivery section of the tubular body ofFIG. 2.

FIG. 9 illustrates a wiring diagram for connecting a plurality oftemperature sensors with a common wire.

FIG. 10 is a block diagram of a feedback control system for use with anultrasonic catheter.

FIG. 11A is a side view of a treatment site.

FIG. 11B is a side view of the distal end of an ultrasonic catheterpositioned at the treatment site of FIG. 11A.

FIG. 11C is a cross-sectional view of the distal end of the ultrasoniccatheter of FIG. 11B positioned at the treatment site before atreatment.

FIG. 11D is a cross-sectional view of the distal end of the ultrasoniccatheter of FIG. 11C, wherein an inner core has been inserted into thetubular body to perform a treatment.

FIG. 12A is a cross-sectional view of a distal end of an ultrasoniccatheter configured for use within small vessels of a patient'svasculature.

FIG. 12B is a cross-sectional view of the ultrasonic catheter of FIG.12A taken through line 12B-12B.

FIG. 13 is a cross-sectional view of an ultrasound radiating memberseparated from a delivery lumen by a chamber.

FIG. 14 is a cross-sectional view of an exemplary technique for applyingultrasonic energy to an infused microbubble therapeutic compound.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

As set forth above, methods and apparatuses have been developed thatallow a vascular occlusion to be treated using both ultrasonic energyand a therapeutic compound having a controlled temperature. Disclosedherein are several exemplary embodiments of ultrasonic catheters thatcan be used to enhance the efficacy of therapeutic compounds at atreatment site within a patient's body. Also disclosed are exemplarymethods for using such catheters. For example, as discussed in greaterdetail below, the ultrasonic catheters disclosed herein can be used todeliver a therapeutic compound having an elevated temperature, or toheat a therapeutic compound after it has been delivered at a treatmentsite within the patient's vasculature.

Introduction

As used herein, the term “therapeutic compound” refers broadly, withoutlimitation, and in addition to its ordinary meaning, to a drug,medicament, dissolution compound, genetic material or any othersubstance capable of effecting physiological functions. Additionally, amixture includes substances such as these is also encompassed withinthis definition of “therapeutic compound”. Examples of therapeuticcompounds include thrombolytic compounds, anti-thrombosis compounds, andother compounds used in the treatment of vascular occlusions, includingcompounds intended to prevent or reduce clot formation. In applicationswhere human blood vessels that have become partially or completelyoccluded by plaque, thrombi, emboli or other substances that reduce theblood carrying capacity of a vessel, exemplary therapeutic compoundsinclude, but are not limited to, heparin, urokinase, streptokinase, tPA,rtPA and BB-10153 (manufactured by British Biotech, Oxford, UK).

As used herein, the terms “ultrasonic energy”, “ultrasound” and“ultrasonic” refer broadly, without limitation, and in addition to theirordinary meaning, to mechanical energy transferred through longitudinalpressure or compression waves. Ultrasonic energy can be emitted ascontinuous or pulsed waves, depending on the parameters of a particularapplication. Additionally, ultrasonic energy can be emitted in waveformshaving various shapes, such as sinusoidal waves, triangle waves, squarewaves, or other wave forms. Ultrasonic energy includes sound waves. Incertain embodiments, the ultrasonic energy referred to herein has afrequency between about 20 kHz and about 20 MHz. For example, in oneembodiment, the ultrasonic energy has a frequency between about 500 kHzand about 20 MHz. In another embodiment, the ultrasonic energy has afrequency between about 1 MHz and about 3 MHz. In yet anotherembodiment, the ultrasonic energy has a frequency of about 2 MHz. Incertain embodiments described herein, the average acoustic power of theultrasonic energy is between about 0.01 watts and 300 watts. In oneembodiment, the average acoustic power is about 15 watts.

As used herein, the term “ultrasound radiating member” refers broadly,without limitation, and in addition to its ordinary meaning, to anyapparatus capable of producing ultrasonic energy. An ultrasonictransducer, which converts electrical energy into ultrasonic energy, isan example of an ultrasound radiating member. An exemplary ultrasonictransducer capable of generating ultrasonic energy from electricalenergy is a piezoelectric ceramic oscillator. Piezoelectric ceramicstypically comprise a crystalline material, such as quartz, that changesshape when an electrical current is applied to the material. This changein shape, made oscillatory by an oscillating driving signal, createsultrasonic sound waves. In other embodiments, ultrasonic energy can begenerated by an ultrasonic transducer that is remote from the ultrasoundradiating member, and the ultrasonic energy can be transmitted, via, forexample, a wire that is coupled to the ultrasound radiating member.

In certain applications, the ultrasonic energy itself provides atherapeutic effect to the patient. Examples of such therapeutic effectsinclude preventing or reducing stenosis and/or restenosis; tissueablation, abrasion or disruption; promoting temporary or permanentphysiological changes in intracellular or intercellular structures; andrupturing micro-balloons or micro-bubbles for therapeutic compounddelivery. Further information about such methods can be found in U.S.Pat. Nos. 5,261,291 and 5,431,663.

The ultrasonic catheters described herein can be configured forapplication of ultrasonic energy over a substantial length of a bodylumen, such as, for example, the larger vessels located in the leg. Inother embodiments, the ultrasonic catheters described herein can beconfigured to be inserted into the small cerebral vessels, in solidtissues, in duct systems and in body cavities. Additional embodimentsthat can be combined with certain features and aspects of theembodiments described herein are described in U.S. patent applicationSer. No. 10/291,891, filed 7 Nov. 2002, the entire disclosure of whichis hereby incorporated herein by reference.

Overview of a Large Vessel Ultrasonic Catheter.

FIG. 1 schematically illustrates an ultrasonic catheter 10 configuredfor use in the large vessels of a patient's anatomy. For example, theultrasonic catheter 10 illustrated in FIG. 1 can be used to treat longsegment peripheral arterial occlusions, such as those in the vascularsystem of the leg.

As illustrated in FIG. 1, the ultrasonic catheter 10 generally includesa multi-component, elongate flexible tubular body 12 having a proximalregion 14 and a distal region 15. The tubular body 12 includes aflexible energy delivery section 18 located in the distal region 15. Thetubular body 12 and other components of the catheter 10 can bemanufactured in accordance with a variety of techniques known to anordinarily skilled artisan. Suitable materials and dimensions can bereadily selected based on the natural and anatomical dimensions of thetreatment site and on the desired percutaneous access site.

For example, in an exemplary embodiment, the tubular body proximalregion 14 comprises a material that has sufficient flexibility, kinkresistance, rigidity and structural support to push the energy deliverysection 18 through the patient's vasculature to a treatment site.Examples of such materials include, but are not limited to, extrudedpolytetrafluoroethylene (“PTFE”), polyethylenes (“PE”), polyamides andother similar materials. In certain embodiments, the tubular bodyproximal region 14 is reinforced by braiding, mesh or otherconstructions to provide increased kink resistance and ability to bepushed. For example, nickel titanium or stainless steel wires can beplaced along or incorporated into the tubular body 12 to reduce kinking.

For example, in an embodiment configured for treating thrombus in thearteries of the leg, the tubular body 12 has an outside diameter betweenabout 0.060 inches and about 0.075 inches. In another embodiment, thetubular body 12 has an outside diameter of about 0.071 inches. Incertain embodiments, the tubular body 12 has an axial length ofapproximately 105 centimeters, although other lengths can be used inother applications.

In an exemplary embodiment, the tubular body energy delivery section 18comprises a material that is thinner than the material comprising thetubular body proximal region 14. In another exemplary embodiment, thetubular body energy delivery section 18 comprises a material that has agreater acoustic transparency than the material comprising the tubularbody proximal region 14. Thinner materials generally have greateracoustic transparency than thicker materials. Suitable materials for theenergy delivery section 18 include, but are not limited to, high or lowdensity polyethylenes, urethanes, nylons, and the like. In certainmodified embodiments, the energy delivery section 18 comprises the samematerial or a material of the same thickness as the proximal region 18.

In an exemplary embodiment, the tubular body 12 is divided into at leastthree sections of varying stiffness. The first section, which includesthe proximal region 14, has a relatively higher stiffness. The secondsection, which is located in an intermediate region between the proximalregion 14 and the distal region 15, has a relatively lower stiffness.This configuration further facilitates movement and placement of thecatheter 10. The third section, which includes the energy deliverysection 18, has a relatively lower stiffness than the second section inspite of the presence of ultrasound radiating members which can bepositioned therein.

FIG. 2 illustrates a cross section of the tubular body 12 taken alongline 2-2 in FIG. 1. In the embodiment illustrated in FIG. 2, three fluiddelivery lumens 30 are incorporated into the tubular body 12. In otherembodiments, more or fewer fluid delivery lumens can be incorporatedinto the tubular body 12. In such embodiments, the arrangement of thefluid delivery lumens 30 provides a hollow central lumen 51 passingthrough the tubular body 12. The cross-section of the tubular body 12,as illustrated in FIG. 2, is substantially constant along the length ofthe catheter 10. Thus, in such embodiments, substantially the samecross-section is present in both the proximal region 14 and the distalregion 15 of the tubular body 12, including the energy delivery section18.

In certain embodiments, the central lumen 51 has a minimum diametergreater than about 0.030 inches. In another embodiment, the centrallumen 51 has a minimum diameter greater than about 0.037 inches. In anexemplary embodiment, the fluid delivery lumens 30 have dimensions ofabout 0.026 inches wide by about 0.0075 inches high, although otherdimensions can be used in other embodiments.

In an exemplary embodiment, the central lumen 51 extends through thelength of the tubular body 12. As illustrated in FIG. 1, the centrallumen 51 has a distal exit port 29 and a proximal access port 31. Theproximal access port 31 forms part of the backend hub 33, which isattached to the tubular body proximal region 14. In such embodiments,the backend hub also includes a cooling fluid fitting 46, which ishydraulically connected to the central lumen 51. In such embodiments,the backend hub 33 also includes a therapeutic compound inlet port 32,which is hydraulically coupled to the fluid delivery lumens 30, andwhich can also be hydraulically coupled to a source of therapeuticcompound via a hub such as a Luer fitting.

The central lumen 51 is configured to receive an elongate inner core 34,an exemplary embodiment of which is illustrated in FIG. 3. In suchembodiments, the elongate inner core 34 includes a proximal region 36and a distal region 38. A proximal hub 37 is fitted on one end of theinner core proximal region 36. One or more ultrasound radiating members40 are positioned within an inner core energy delivery section 41 thatis located within the distal region 38. The ultrasound radiating members40 form an ultrasound assembly 42, which will be described in greaterdetail below.

As shown in the cross-section illustrated in FIG. 4, which is takenalong lines 4-4 in FIG. 3, in an exemplary embodiment, the inner core 34has a cylindrical shape, with an outer diameter that permits the innercore 34 to be inserted into the central lumen 51 of the tubular body 12via the proximal access port 31. Suitable outer diameters of the innercore 34 include, but are not limited to, between about 0.010 inches andabout 0.100 inches. In another embodiment, the outer diameter of theinner core 34 is between about 0.020 inches and about 0.080 inches. Inyet another embodiment, the inner core 34 has an outer diameter of about0.035 inches.

Still referring to FIG. 4, the inner core 34 includes a cylindricalouter body 35 that houses the ultrasound assembly 42. The ultrasoundassembly 42 includes wiring and ultrasound radiating members, describedin greater detail in FIGS. 5 through 7D, such that the ultrasoundassembly 42 is capable of radiating ultrasonic energy from the energydelivery section 41 of the inner core 34. The ultrasound assembly 42 iselectrically connected to the backend hub 33, where the inner core 34can be connected to a control system 100 via cable 45 (illustrated inFIG. 1). In an exemplary embodiment, an electrically insulating pottingmaterial 43 fills the inner core 34, surrounding the ultrasound assembly42, thus reducing or preventing movement of the ultrasound assembly 42with respect to the outer body 35. In one embodiment, the thickness ofthe outer body 35 is between about 0.0002 inches and 0.010 inches. Inanother embodiment, the thickness of the outer body 35 is between about0.0002 inches and 0.005 inches. In yet another embodiment, the thicknessof the outer body 35 is about 0.0005 inches.

In an exemplary embodiment, the ultrasound assembly 42 includes aplurality of ultrasound radiating members 40 that are divided into oneor more groups. For example, FIGS. 5 and 6 are schematic wiring diagramsillustrating one technique for connecting five groups of ultrasoundradiating members 40 to form the ultrasound assembly 42. As illustratedin FIG. 5, the ultrasound assembly 42 comprises five groups G1, G2, G3,G4, G5 of ultrasound radiating members 40 that are electricallyconnected to each other. The five groups are also electrically connectedto the control system 100.

Still referring to FIG. 5, in an exemplary embodiment, the controlcircuitry 100 includes a voltage source 102 having a positive terminal104 and a negative terminal 106. The negative terminal 106 is connectedto common wire 108, which connects the five groups G1-G5 of ultrasoundradiating members 40 in series. The positive terminal 104 is connectedto a plurality of lead wires 110, which each connect to one of the fivegroups G1-G5 of ultrasound radiating members 40. Thus, under thisconfiguration, each of the five groups G1-G5, one of which isillustrated in FIG. 6, is connected to the positive terminal 104 via oneof the lead wires 110, and to the negative terminal 106 via the commonwire 108.

Referring now to FIG. 6, each group G1-G5 includes a plurality ofultrasound radiating members 40. Each of the ultrasound radiatingmembers 40 is electrically connected to the common wire 108 and to thelead wire 110 via a positive contact wires 112. Thus, when wired asillustrated, a substantially constant voltage difference will be appliedto each ultrasound radiating member 40 in the group. Although the groupillustrated in FIG. 6 includes twelve ultrasound radiating members 40,in other embodiments, more or fewer ultrasound radiating members 40 canbe included in the group. Likewise, more or fewer than five groups canbe included within the ultrasound assembly 42 illustrated in FIG. 5.

FIG. 7A illustrates an exemplary technique for arranging the componentsof the ultrasound assembly 42 (as schematically illustrated in FIG. 5)into the inner core 34 (as schematically illustrated in FIG. 4). FIG. 7Ais a cross-sectional view of the ultrasound assembly 42 taken withingroup G1 in FIG. 5, as indicated by the presence of four lead wires 110.For example, if a cross-sectional view of the ultrasound assembly 42 wastaken within group G4 in FIG. 5, only one lead wire 110 would be present(that is, the one lead wire connecting group G5).

In the exemplary embodiment illustrated in FIG. 7A, the common wire 108includes an elongate, flat piece of electrically conductive material inelectrical contact with a pair of ultrasound radiating members 40. Eachof the ultrasound radiating members 40 is also in electrical contactwith a positive contact wire 112. Because the common wire 108 isconnected to the negative terminal 106, and the positive contact wire112 is connected to the positive terminal 104, a voltage difference canbe created across each ultrasound radiating member 40. In suchembodiments, lead wires 110 are separated from the other components ofthe ultrasound assembly 42, thus preventing interference with theoperation of the ultrasound radiating members 40 as described above. Forexample, in an exemplary embodiment, the inner core 34 is filled with aninsulating potting material 43, thus deterring unwanted electricalcontact between the various components of the ultrasound assembly 42.

FIGS. 7B and 7C illustrate cross sectional views of the inner core 34 ofFIG. 7A taken along lines 7B-7B and 7C-7C, respectively. As illustratedin FIG. 7B, the ultrasound radiating members 40 are mounted in pairsalong the common wire 108. The ultrasound radiating members 40 areconnected by positive contact wires 112, such that substantially thesame voltage is applied to each ultrasound radiating member 40. Asillustrated in FIG. 7C, the common wire 108 includes wide regions 108Wupon which the ultrasound radiating members 40 can be mounted, thusreducing the likelihood that the paired ultrasound radiating members 40will short together. In certain embodiments, outside the wide regions108W, the common wire 108 can have a more conventional, rounded wireshape.

In a modified embodiment, such as illustrated in FIG. 7D, the commonwire 108 is twisted to form a helical shape before being fixed withinthe inner core 34. In such embodiments, the ultrasound radiating members40 are oriented in a plurality of radial directions, thus enhancing theradial uniformity of the resulting ultrasonic energy field.

The wiring arrangement described above can be modified to allow eachgroup G1, G2, G3, G4, G5 to be independently powered. Specifically, byproviding a separate power source within the control system 100 for eachgroup, each group can be individually turned on or off, or can be drivenat an individualized power level. This advantageously allows thedelivery of ultrasonic energy to be “turned off” in regions of thetreatment site where treatment is complete, thus preventing deleteriousor unnecessary ultrasonic energy to be applied to the patient.

The embodiments described above, and illustrated in FIGS. 5 through 7,include a plurality of ultrasound radiating members grouped spatially.That is, in such embodiments, the ultrasound radiating members within acertain group are positioned adjacent to each other, such that when asingle group is activated, ultrasonic energy is delivered from a certainlength of the ultrasound assembly. However, in modified embodiments, theultrasound radiating members of a certain group may be spaced apart fromeach other, such that the ultrasound radiating members within a certaingroup are not positioned adjacent to each other. In such embodiments,when a single group is activated, ultrasonic energy can be deliveredfrom a larger, spaced apart portion of the ultrasound assembly. Suchmodified embodiments can be advantageous in applications where a lessfocussed, more diffuse ultrasonic energy field is to be delivered to thetreatment site.

In an exemplary embodiment, the ultrasound radiating members 40 compriserectangular lead zirconate titanate (“PZT”) ultrasound transducers thathave dimensions of about 0.017 inches by about 0.010 inches by about0.080 inches. In other embodiments, other configurations and dimensionscan be used. For example, disc-shaped ultrasound radiating members 40can be used in other embodiments. In an exemplary embodiment, the commonwire 108 comprises copper, and is about 0.005 inches thick, althoughother electrically conductive materials and other dimensions can be usedin other embodiments. In an exemplary embodiment, lead wires 110 are 36gauge electrical conductors, and positive contact wires 112 are 42 gaugeelectrical conductors. However, other wire gauges can be used in otherembodiments.

As described above, suitable frequencies for the ultrasound radiatingmembers 40 include, but are not limited to, from about 20 kHz to about20 MHz. In one embodiment, the frequency is between about 500 kHz andabout 20 MHz, and in another embodiment the frequency is between about 1MHz and about 3 MHz. In yet another embodiment, the ultrasound radiatingmembers 40 are operated with a frequency of about 2 MHz.

FIG. 8 illustrates the inner core 34 positioned within the tubular body12. Details of the ultrasound assembly 42, provided in FIG. 7A, areomitted for clarity. As described above, the inner core 34 can be slidwithin the central lumen 51 of the tubular body 12, thereby allowing theinner core energy delivery section 41 to be positioned within thetubular body energy delivery section 18. For example, in an exemplaryembodiment, the materials comprising the inner core energy deliverysection 41, the tubular body energy delivery section 18, and the pottingmaterial 43 all comprise materials having a similar acoustic impedance,thereby minimizing ultrasonic energy losses across material interfaces.

FIG. 8 further illustrates placement of fluid delivery ports 58 withinthe tubular body energy delivery section 18. As illustrated, holes orslits are formed from the fluid delivery lumen 30 through the tubularbody 12, thereby permitting fluid flow from the fluid delivery lumen 30to the treatment site. A plurality of fluid delivery ports 58 can bepositioned axially along the tubular body 12. Thus, a source oftherapeutic compound coupled to the inlet port 32 provides a hydraulicpressure which drives the therapeutic compound through the fluiddelivery lumens 30 and out the fluid delivery ports 58.

By spacing the fluid delivery lumens 30 around the circumference of thetubular body 12 substantially evenly, as illustrated in FIG. 8, asubstantially uniform flow of therapeutic compound around thecircumference of the tubular body 12 can be achieved. Additionally, thesize, location and geometry of the fluid delivery ports 58 can beselected to provide uniform fluid flow from the fluid delivery ports 30to the treatment site. For example, in one embodiment, fluid deliveryports closer to the proximal region of the energy delivery section 18have smaller diameters than fluid delivery ports closer to the distalregion of the energy delivery section 18, thereby allowing uniformdelivery of therapeutic compound in the energy delivery section.

For example, in one embodiment in which the fluid delivery ports 58 havesimilar sizes along the length of the tubular body 12, the fluiddelivery ports 58 have a diameter between about 0.0005 inches to about0.0050 inches. In another embodiment in which the size of the fluiddelivery ports 58 changes along the length of the tubular body 12, thefluid delivery ports 58 have a diameter between about 0.001 inches toabout 0.005 inches in the proximal region of the energy delivery section18, and between about 0.005 inches to about 0.0020 inches in the distalregion of the energy delivery section 18. The increase in size betweenadjacent fluid delivery ports 58 depends on a variety of factors,including the material comprising the tubular body 12, and on the sizeof the fluid delivery lumen 30. The fluid delivery ports 58 can becreated in the tubular body 12 by punching, drilling, burning orablating (such as with a laser), or by other suitable methods.Therapeutic compound flow along the length of the tubular body 12 canalso be increased by increasing the density of the fluid delivery ports58 toward the distal region of the energy delivery section.

In certain applications, a spatially nonuniform flow of therapeuticcompound from the fluid delivery ports 58 to the treatment site is to beprovided. In such applications, the size, location and geometry of thefluid delivery ports 58 can be selected to provide such nonuniform fluidflow.

Referring still to FIG. 8, placement of the inner core 34 within thetubular body 12 further defines cooling fluid lumens 44. Cooling fluidlumens 44 are formed between an outer surface 39 of the inner core 34and an inner surface 16 of the tubular body 12. In certain embodiments,a cooling fluid is introduced through the proximal access port 31 suchthat cooling fluid flows through cooling fluid lumens 44 and out of thecatheter 10 through distal exit port 29 (see FIG. 1). In an exemplaryembodiment, the cooling fluid lumens 44 are substantially evenly spacedaround the circumference of the tubular body 12 (that is, atapproximately 120° increments for a three-lumen configuration), therebyproviding substantially uniform cooling fluid flow over the inner core34. Such a configuration advantageously removes thermal energy from thetreatment site. As will be explained below, the flow rate of the coolingfluid and the power to the ultrasound assembly 42 can be adjusted tomaintain the temperature of the inner core energy delivery section 41,or of the treatment site generally, within a desired range.

In an exemplary embodiment, the inner core 34 can be rotated or movedwithin the tubular body 12. Specifically, movement of the inner core 34can be accomplished by maneuvering the proximal hub 37 while holding thebackend hub 33 stationary. The inner core outer body 35 is at leastpartially constructed from a material that provides enough structuralsupport to permit movement of the inner core 34 within the tubular body12 without kinking of the tubular body 12. Additionally, in an exemplaryembodiment, the inner core outer body 35 comprises a material having theability to transmit torque. Suitable materials for the inner core outerbody 35 include, but are not limited to, polyimides, polyesters,polyurethanes, thermoplastic elastomers and braided polyimides.

In an exemplary embodiment, the fluid delivery lumens 30 and the coolingfluid lumens 44 are open at the distal end of the tubular body 12,thereby allowing the therapeutic compound and the cooling fluid to passinto the patient's vasculature at the distal exit port 29. In a modifiedembodiment, the fluid delivery lumens 30 can be selectively occluded atthe distal end of the tubular body 12, thereby providing additionalhydraulic pressure to drive the therapeutic compound out of the fluiddelivery ports 58. In either configuration, the inner core 34 can beprevented from passing through the distal exit port 29 by providing theinner core 34 with a length that is less than the length of the tubularbody 12. In other embodiments, a protrusion is formed within the tubularbody 12 in the distal region 15, thereby preventing the inner core 34from passing through the distal exit port 29.

In other embodiments, the catheter 10 includes an occlusion devicepositioned at the distal exit port 29. In such embodiments, theocclusion device has a reduced inner diameter that can accommodate aguidewire, but that is less than the inner diameter of the central lumen51. Thus, the inner core 34 is prevented from extending past theocclusion device and out the distal exit port 29. For example, suitableinner diameters for the occlusion device include, but are not limitedto, between about 0.005 inches and about 0.050 inches. In otherembodiments, the occlusion device has a closed end, thus preventingcooling fluid from leaving the catheter 10, and instead recirculating tothe tubular body proximal region 14. These and other cooling fluid flowconfigurations permit the power provided to the ultrasound assembly 42to be increased in proportion to the cooling fluid flow rate.Additionally, certain cooling fluid flow configurations can reduceexposure of the patient's body to cooling fluids.

In an exemplary embodiment, such as illustrated in FIG. 8, the tubularbody 12 includes one or more temperature sensors 20 that are positionedwithin the energy delivery section 18. In such embodiments, the tubularbody proximal region 14 includes a temperature sensor lead which can beincorporated into cable 45 (illustrated in FIG. 1). Suitable temperaturesensors include, but are not limited to, temperature sensing diodes,thermistors, thermocouples, resistance temperature detectors (“RTDs”)and fiber optic temperature sensors which use thermalchromic liquidcrystals. Suitable temperature sensor 20 geometries include, but are notlimited to, a point, a patch or a stripe. The temperature sensors 20 canbe positioned within one or more of the fluid delivery lumens 30, and/orwithin one or more of the cooling fluid lumens 44.

FIG. 9 illustrates an exemplary embodiment for electrically connectingthe temperature sensors 20. In such embodiments, each temperature sensor20 is coupled to a common wire 61 and is associated with an individualreturn wire 62. Accordingly, n+1 wires are passed through the tubularbody 12 to independently sense the temperature at n temperature sensors20. The temperature at a selected temperature sensor 20 can bedetermined by closing a switch 64 to complete a circuit between thereturn wire 62 associated with the selected thermocouple and the commonwire 61. In embodiments wherein the temperature sensors 20 arethermocouples, the temperature can be calculated from the voltage in thecircuit using, for example, a sensing circuit 63, which can be locatedwithin the external control circuitry 100.

In other embodiments, the temperature sensors 20 can be independentlywired. In such embodiments, 2n wires are passed through the tubular body12 to independently sense the temperature at n temperature sensors 20.In still other embodiments, the flexibility of the tubular body 12 canbe improved by using fiber optic based temperature sensors 20. In suchembodiments, flexibility can be improved because only n fiber opticmembers are used to sense the temperature at n independent temperaturesensors 20.

FIG. 10 schematically illustrates one embodiment of a feedback controlsystem 68 that can be used with the catheter 10. The feedback controlsystem 68 can be integrated into the control system 100 that isconnected to the inner core 34 via cable 45 (as illustrated in FIG. 1).The feedback control system 68 allows the temperature at eachtemperature sensor 20 to be monitored and allows the output power of theenergy source 70 to be adjusted accordingly. A physician can, ifdesired, override the closed or open loop system.

In an exemplary embodiment, the feedback control system 68 includes anenergy source 70, power circuits 72 and a power calculation device 74that is coupled to the ultrasound radiating members 40. A temperaturemeasurement device 76 is coupled to the temperature sensors 20 in thetubular body 12. A processing unit 78 is coupled to the powercalculation device 74, the power circuits 72 and a user interface anddisplay 80.

In an exemplary method of operation, the temperature at each temperaturesensor 20 is determined by the temperature measurement device 76. Theprocessing unit 78 receives each determined temperature from thetemperature measurement device 76. The determined temperature can thenbe displayed to the user at the user interface and display 80.

In an exemplary embodiment, the processing unit 78 includes logic forgenerating a temperature control signal. The temperature control signalis proportional to the difference between the measured temperature and adesired temperature. The desired temperature can be determined by theuser (as set at the user interface and display 80) or can be presetwithin the processing unit 78.

In such embodiments, the temperature control signal is received by thepower circuits 72. The power circuits 72 are configured to adjust thepower level, voltage, phase and/or current of the electrical energysupplied to the ultrasound radiating members 40 from the energy source70. For example, when the temperature control signal is above aparticular level, the power supplied to a particular group of ultrasoundradiating members 40 is reduced in response to that temperature controlsignal. Similarly, when the temperature control signal is below aparticular level, the power supplied to a particular group of ultrasoundradiating members 40 is increased in response to that temperaturecontrol signal. After each power adjustment, the processing unit 78monitors the temperature sensors 20 and produces another temperaturecontrol signal which is received by the power circuits 72.

In an exemplary embodiment, the processing unit 78 optionally includessafety control logic. The safety control logic detects when thetemperature at a temperature sensor 20 exceeds a safety threshold. Inthis case, the processing unit 78 can be configured to provide atemperature control signal which causes the power circuits 72 to stopthe delivery of energy from the energy source 70 to that particulargroup of ultrasound radiating members 40.

Because, in certain embodiments, the ultrasound radiating members 40 aremobile relative to the temperature sensors 20, it can be unclear whichgroup of ultrasound radiating members 40 should have a power, voltage,phase and/or current level adjustment. Consequently, each group ofultrasound radiating members 40 can be identically adjusted in certainembodiments. For example, in a modified embodiment, the power, voltage,phase, and/or current supplied to each group of ultrasound radiatingmembers 40 is adjusted in response to the temperature sensor 20 whichindicates the highest temperature. Making voltage, phase and/or currentadjustments in response to the temperature sensed by the temperaturesensor 20 indicating the highest temperature can reduce overheating ofthe treatment site.

The processing unit 78 can also be configured to receive a power signalfrom the power calculation device 74. The power signal can be used todetermine the power being received by each group of ultrasound radiatingmembers 40. The determined power can then be displayed to the user onthe user interface and display 80.

As described above, the feedback control system 68 can be configured tomaintain tissue adjacent to the energy delivery section 18 below adesired temperature. For example, in certain applications, tissue at thetreatment site is to have a temperature increase of less than or equalto approximately 6° C. As described above, the ultrasound radiatingmembers 40 can be electrically connected such that each group ofultrasound radiating members 40 generates an independent output. Incertain embodiments, the output from the power circuit maintains aselected energy for each group of ultrasound radiating members 40 for aselected length of time.

The processing unit 78 can comprise a digital or analog controller, suchas a computer with software. In embodiments wherein the processing unit78 is a computer, the computer can include a central processing unit(“CPU”) coupled through a system bus. In such embodiments, the userinterface and display 80 can include a mouse, a keyboard, a disk drive,a display monitor, a nonvolatile memory system, and/or other computercomponents. In an exemplary embodiment, program memory and/or datamemory is also coupled to the bus.

In another embodiment, in lieu of the series of power adjustmentsdescribed above, a profile of the power to be delivered to each group ofultrasound radiating members 40 can be incorporated into the processingunit 78, such that a preset amount of ultrasonic energy to be deliveredis pre-profiled. In such embodiments, the power delivered to each groupof ultrasound radiating members 40 is provided according to the presetprofiles.

In an exemplary embodiment, the ultrasound radiating members areoperated in a pulsed mode. For example, in one embodiment, the timeaverage power supplied to the ultrasound radiating members is betweenabout 0.1 watts and about 2 watts. In another embodiment, the timeaverage power supplied to the ultrasound radiating members is betweenabout 0.5 watts and about 1.5 watts. In yet another embodiment, the timeaverage power supplied to the ultrasound radiating members isapproximately 0.6 watts or approximately 1.2 watts. In an exemplaryembodiment, the duty cycle is between about 1% and about 50%. In anotherembodiment, the duty cycle is between about 5% and about 25%. In yetanother embodiment, the duty cycles is approximately 7.5% orapproximately 15%. In an exemplary embodiment, the pulse averaged poweris between about 0.1 watts and about 20 watts. In another embodiment,the pulse averaged power is between approximately 5 watts andapproximately 20 watts. In yet another embodiment, the pulse averagedpower is approximately 8 watts or approximately 16 watts. The amplitudeduring each pulse can be constant or varied.

In an exemplary embodiment, the pulse repetition rate is between about 5Hz and about 150 Hz. In another embodiment, the pulse repetition rate isbetween about 10 Hz and about 50 Hz. In yet another embodiment, thepulse repetition rate is approximately 30 Hz. In an exemplaryembodiment, the pulse duration is between about 1 millisecond and about50 milliseconds. In another embodiment, the pulse duration is betweenabout 1 millisecond and about 25 milliseconds. In yet anotherembodiment, the pulse duration is approximately 2.5 milliseconds orapproximately 5 milliseconds.

For example, in one particular embodiment, the ultrasound radiatingmembers are operated at an average power of approximately 0.6 watts, aduty cycle of approximately 7.5%, a pulse repetition rate ofapproximately 30 Hz, a pulse average electrical power of approximately 8watts and a pulse duration of approximately 2.5 milliseconds.

In an exemplary embodiment, the ultrasound radiating member used withthe electrical parameters described herein has an acoustic efficiencygreater than approximately 50%. In another embodiment, the ultrasoundradiating member used with the electrical parameters described hereinhas an acoustic efficiency greater than approximately 75%. As describedherein, the ultrasound radiating members can be formed in a variety ofshapes, such as, cylindrical (solid or hollow), flat, bar, triangular,and the like. In an exemplary embodiment, the length of the ultrasoundradiating member is between about 0.1 cm and about 0.5 cm, and thethickness or diameter of the ultrasound radiating member is betweenabout 0.02 cm and about 0.2 cm.

FIGS. 11A through 11D illustrate an exemplary method for using certainembodiments of the ultrasonic catheter 10 describe herein. Asillustrated in FIG. 11A, a guidewire 84 similar to a guidewire used intypical angioplasty procedures is directed through a patient's vessels86 to a treatment site 88 that includes a clot 90. The guidewire 84 isoptionally directed through the clot 90. Suitable vessels 86 include,but are not limited to, the large periphery blood vessels of the body.Additionally, as mentioned above, the ultrasonic catheter 10 also hasutility in various imaging applications or in applications for treatingand/or diagnosing other diseases in other body parts.

As illustrated in FIG. 11B, the tubular body 12 is slid over and isadvanced along the guidewire 84, for example using conventionalover-the-guidewire techniques. The tubular body 12 is advanced until theenergy delivery section 18 is positioned at the clot 90. In certainembodiments, radiopaque markers (not shown) are optionally positionedalong the tubular body energy delivery section 18 to aid in thepositioning of the tubular body 12 within the treatment site 88.

As illustrated in FIG. 10C, after the tubular body 12 is delivered tothe treatment site 88, the guidewire 84 is withdrawn from the tubularbody 12 by pulling the guidewire 84 from the proximal region 14 of thecatheter 10 while holding the tubular body 12 stationary. This leavesthe tubular body 12 positioned at the treatment site 88.

As illustrated in FIG. 10D, the inner core 34 is then inserted into thetubular body 12 until the ultrasound assembly 42 is positioned at leastpartially within the energy delivery section 18. In one embodiment, theultrasound assembly 42 can be configured to be positioned at leastpartially within the energy delivery section 18 when the inner core 24abuts the occlusion device at the distal end of the tubular body 12.Once the inner core 34 is positioned in such that the ultrasoundassembly 42 is at least partially within the energy delivery section,the ultrasound assembly 42 is activated to deliver ultrasonic energy tothe clot 90. As described above, in one embodiment, ultrasonic energyhaving a frequency between about 20 kHz and about 20 MHz is delivered tothe treatment site.

In an exemplary embodiment, the ultrasound assembly 42 includes sixtyultrasound radiating members 40 spaced over a length of approximately 30to approximately 50 cm. In such embodiments, the catheter 10 can be usedto treat an elongate clot 90 without requiring moving or repositioningthe catheter 10 during the treatment. However, in modified embodiments,the inner core 34 can be moved or rotated within the tubular body 12during the treatment. Such movement can be accomplished by maneuveringthe proximal hub 37 of the inner core 34 while holding the backend hub33 stationary.

Still referring to FIG. 11D, arrows 48 indicate that a cooling fluid canbe delivered through the cooling fluid lumen 44 and out the distal exitport 29. Likewise, arrows 49 indicate that a therapeutic compound can bedelivered through the fluid delivery lumen 30 and out the fluid deliveryports 58 to the treatment site 88.

The cooling fluid can be delivered before, after, during orintermittently with the delivery of ultrasonic energy. Similarly, thetherapeutic compound can be delivered before, after, during orintermittently with the delivery of ultrasonic energy. Consequently, themethods illustrated in FIGS. 11A through 11D can be performed in avariety of different orders than that described above. In an exemplaryembodiment, the therapeutic compound and ultrasonic energy are delivereduntil the clot 90 is partially or entirely dissolved. Once the clot 90has been sufficiently dissolved, the tubular body 12 and the inner core34 are withdrawn from the treatment site 88.

Overview of a Small Vessel Ultrasonic Catheter.

Ultrasonic catheters can also be specifically configured to use in thesmall vessels of a patient's vasculature, such as in the vasculature ofa patient's brain. In such a configuration, the catheter is providedwith an energy delivery section having increased flexibility, therebyfacilitating delivery of the catheter through narrow vessels havingsmall radius turns. FIGS. 12A and 12B are cross-sectional views of thedistal region of an exemplary ultrasonic catheter configured for use inthe small vasculature.

Similar to the large vessel ultrasonic catheter described herein, anexemplary ultrasonic catheter configured for use in small vesselscomprises a multi-component tubular body 202 having a proximal regionand a distal region 206. In such embodiments, the catheter tubular body202 includes an outer sheath 208 that is positioned upon an inner core210. In one embodiment, the outer sheath 208 comprises extruded Pebax®,PTFE, polyetheretherketone (“PEEK”), PE, polyamides, braided polyamidesand/or other similar materials. The outer sheath distal region 206 isadapted for advancement through vessels having a small diameter, such asthose in the vasculature of the brain. In an exemplary embodiment, theouter sheath distal region 206 has an outer diameter between about 2French and about 5 French. In another embodiment, outer sheath distalregion 206 has an outer diameter of about 2.8 French. In one exemplaryembodiment, the outer sheath 208 has an axial length of approximately150 centimeters.

In a modified embodiment, the outer sheath 208 comprises a braidedtubing formed of, for example, high or low density polyethylenes,urethanes, nylons, and the like. This configuration enhances theflexibility of the tubular body 202. For enhanced maneuverability,especially the ability to be pushed and rotated, the outer sheath 208can be formed with a variable stiffness from the proximal to the distalend. To achieve this, a stiffening member may be included along theproximal end of the tubular body 202.

The inner core 210 defines, at least in part, a delivery lumen 212,which, in an exemplary embodiment, extends longitudinally along thecatheter. The delivery lumen 212 has a distal exit port 214, and ishydraulically connected to a proximal access port (not shown). Similarto the large vessel ultrasonic catheter described herein, the proximalaccess port can be connected to a source of therapeutic compound orcooling fluid that is to be delivered through the delivery lumen 212.

In an exemplary embodiment, the delivery lumen 212 is configured toreceive a guide wire (not shown). In such embodiments, the guidewire hasa diameter of between approximately 0.008 and approximately 0.012inches. In another embodiment, the guidewire has a diameter of about0.010 inches. In an exemplary embodiment, the inner core 210 comprisespolyamide or a similar material which can optionally be braided toincrease the flexibility of the tubular body 202.

Still referring to FIGS. 12A and 12B, the tubular body distal region 206includes an ultrasound radiating member 224. In such embodiments, theultrasound radiating member 224 comprises an ultrasound transducer,which converts, for example, electrical energy into ultrasonic energy.In a modified embodiment, the ultrasonic energy can be generated by anultrasound transducer that is remote from the ultrasound radiatingmember 224 and the ultrasonic energy can be transmitted via, forexample, a wire to the ultrasound radiating member 224.

In the illustrated embodiment, the ultrasound radiating member 224 isconfigured as a hollow cylinder. As such, the inner core 210 extendsthrough the lumen of the ultrasound radiating member 224. The ultrasoundradiating member 224 is secured to the inner core 210 in a suitablemanner, such as using an adhesive. A potting material can also be usedto further secure the ultrasound radiating member 224 to the inner core210.

In other embodiments, the ultrasound radiating member 224 can have adifferent shape. For example, the ultrasound radiating member 224 cantake the form of a solid rod, a disk, a solid rectangle or a thin block.In still other embodiments, the ultrasound radiating member 224 cancomprise a plurality of smaller ultrasound radiating members. Theillustrated configuration advantageously provides enhanced cooling ofthe ultrasound radiating member 224. For example, in one embodiment, atherapeutic compound can be delivered through the delivery lumen 212. Asthe therapeutic compound passes through the lumen of the ultrasoundradiating member 224, the therapeutic compound can advantageously removeexcess heat generated by the ultrasound radiating member 224. In anotherembodiment, a fluid return path can be formed in the region 238 betweenthe outer sheath 208 and the inner core 21 such that coolant from acoolant system can be directed through the region 238.

In an exemplary embodiment, the ultrasound radiating member 224 producesultrasonic energy having a frequency of between about 20 kHz and about20 MHz. In one embodiment, the frequency of the ultrasonic energy isbetween about 500 kHz and about 20 MHz, and in another embodiment thefrequency of the ultrasonic energy is between about 1 MHz and about 3MHz. In yet another embodiment, the ultrasonic energy has a frequency ofabout 3 MHz.

In the illustrated embodiment, ultrasonic energy is generated fromelectrical power supplied to the ultrasound radiating member 224 througha wires 226, 228 that extend through the catheter body 202. The wires226, 228 cab be secured to the inner core 210, lay along the inner core210 and/or extend freely in the region 238 between the inner core 210and the outer sheath 208. In the illustrated configuration, the firstwire 226 is connected to the hollow center of the ultrasound radiatingmember 224, while the second wire 228 is connected to the outerperiphery of the ultrasound radiating member 224. In such embodiments,the ultrasound radiating member 224 comprises a transducer formed of apiezoelectric ceramic oscillator or a similar material.

Still referring to the exemplary embodiment illustrated in FIGS. 12A and12B, the catheter further includes a sleeve 230 that is generallypositioned about the ultrasound radiating member 224. The sleeve 230 iscomprises a material that readily transmits ultrasonic energy. Suitablematerials for the sleeve 230 include, but are not limited to,polyolefins, polyimides, polyester and other materials having arelatively low absorbance of ultrasonic energy. The proximal end of thesleeve 230 can be attached to the outer sheath 208 with an adhesive 232.To improve the bonding of the adhesive 232 to the outer sheath 208, ashoulder 227 or notch can be formed in the outer sheath 208 forattachment of the adhesive 232 thereto. In an exemplary embodiment, theouter sheath 208 and the sleeve 230 have substantially the same outerdiameter.

In a similar manner, the distal end of the sleeve 230 can be attached toa tip 234. As illustrated, the tip 234 is also attached to the distalend of the inner core 210. In an exemplary embodiment, the tip 234 isbetween about 0.5 mm and about 4.0 mm long. In another embodiment, thetip is about 2.0 mm long. In the illustrated exemplary embodiment, thetip 234 is rounded in shape to reduce trauma or damage to tissue alongthe inner wall of a blood vessel or other body structure duringadvancement of the catheter to a treatment site.

Referring now to the exemplary embodiment illustrated in FIG. 12B, thecatheter includes at least one temperature sensor 236 in the tubularbody distal region 206. The temperature sensor 236 can be positioned onor near the ultrasound radiating member 224. Suitable temperaturesensors include but are not limited to, diodes, thermistors,thermocouples, RTDs and fiber optic temperature sensors that usedthermalchromic liquid crystals. In an exemplary embodiment, thetemperature sensor 236 is operatively connected to a control system viaa control wire that extends through the tubular body 202. As describedabove for the large vessel ultrasonic catheter, the control box includesa feedback control system having the ability to monitor and control thepower, voltage, current and phase supplied to the ultrasound radiatingmember 224. Thus, the temperature along the relevant region of thecatheter can be monitored and controlled for optimal performance.Details of the control box can also be found in U.S. patent applicationSer. No. 10/309,388, filed 3 Dec. 2002, the entire disclosure of whichis hereby incorporated herein by reference.

The small vessel ultrasound catheters disclosed herein can be used toremove an occlusion from a small blood vessel. In an exemplary method ofuse, a guidewire is percutaneously inserted into the patient'svasculature at a suitable insertion site. The guidewire is advancedthrough the vasculature toward a treatment site where the vessel iswholly or partially occluded. The guidewire is then directed at leastpartially through the thrombus.

After advancing the guidewire to the treatment site, the catheter isthen inserted into the vasculature through the insertion site, andadvanced along the guidewire towards the treatment site using, forexample, over-the-guidewire techniques. The catheter is advanced untilthe tubular body distal region 206 is positioned near or in theocclusion. The tubular body distal region 206 optionally includes one ormore radiopaque markers to aid in positioning the catheter at thetreatment site.

After placing the catheter at the treatment site, the guidewire can thenbe withdrawn from the delivery lumen 212. A source of therapeuticcompound, such as a syringe with a Luer fitting, can then be attached tothe proximal access port. This allows the therapeutic compound to bedelivered through the delivery lumen 212 and the distal exit port 214 tothe occlusion.

The ultrasound radiating member 224 can then be activated to generateultrasonic energy. As described above, in an exemplary embodiment, theultrasonic energy has a frequency between about 20 kHz and about 20 MHz.In one embodiment, the frequency of the ultrasonic energy is betweenabout 500 kHz and about 20 MHz, and in another embodiment the frequencyof the ultrasonic energy is between about 1 MHz and about 3 MHz. In yetanother embodiment, the ultrasonic energy has a frequency of about 3MHz. The therapeutic compound and ultrasound energy can be applied untilthe occlusion is partially or entirely dissolved. Once the occlusion hasbeen sufficiently dissolved, the catheter can be withdrawn from thetreatment site.

Further information on exemplary methods of use, as well as on modifiedsmall vessel catheter constructions, are available in U.S. patentapplication Ser. No. 10/309,417, filed 3 Dec. 2002, the entiredisclosure of which is hereby incorporated herein by reference.

Treatment of Vascular Occlusions Using Ultrasonic Energy andMicrobubbles.

In certain embodiments, the therapeutic compound delivered to thetreatment site includes a plurality of microbubbles having, for example,a gas formed therein. A therapeutic compound containing microbubbles isreferred to herein as a “microbubble therapeutic compound”. In anexemplary embodiment, the microbubbles are formed by entrapping microspheres of gas into the therapeutic compound. In one embodiment, this isaccomplished by agitating the therapeutic compound while blowing a gasinto the therapeutic compound. In another embodiment, this isaccomplished by exposing the therapeutic compound to ultrasonic energywith a sonicator under a gaseous atmosphere while vibrating thetherapeutic compound. Other techniques can be used in other embodiments.Exemplary gases that are usable to form the microbubbles include, butare not limited to, air, oxygen, carbon dioxide, and inert gases. In oneexemplary embodiment, the therapeutic compound includes approximately4×10⁷ microbubbles per milliliter of liquid. In one exemplaryembodiment, the therapeutic compound includes between approximately4×10⁶ and approximately 4×10⁸ microbubbles per milliliter of liquid. Inone exemplary embodiment the microbubbles have a diameter of betweenapproximately 0.1 μm and approximately 100 μm. Other parameters can beused in other embodiments.

In an exemplary embodiment, the efficacy of the therapeutic compound isenhanced by the presence of the microbubbles contained therein. In oneembodiment, the microbubbles act as a nucleus for cavitation, and thusallow cavitation to be induced at lower levels of ultrasonic energy.Therefore, a reduced amount of ultrasonic energy can be delivered to thetreatment site without reducing the efficacy of the treatment. Reducingthe amount of ultrasonic energy delivered to the treatment site reducesrisks associated with overheating the treatment site, and, in certainembodiments, also reduces the time required to treat a vascularocclusion. In certain embodiments, cavitation also promotes moreeffective diffusion and penetration of the therapeutic compound intosurrounding tissues, such as the vessel wall and/or the clot material.Furthermore, in some embodiments, the mechanical agitation caused motionof the microbubbles is effective in mechanically breaking up clotmaterial.

In an exemplary embodiment, a therapeutic compound containingmicrobubbles is delivered using the various embodiments of theultrasonic catheters disclosed herein. However, in certain embodiments,modifications to the catheter design, and/or to the method of use, areimplemented to improve the efficacy of a microbubble-based vascularocclusion treatment. In particular, these modifications are intended toreduce the destruction of microbubbles within the ultrasonic catheter.For example, the microbubbles occasionally burst when exposed toultrasonic energy, regardless of whether that exposure occurs inside oroutside the fluid delivery lumens of the ultrasonic catheter. Therefore,these modifications are intended to reduce the exposure of themicrobubble therapeutic compound to ultrasonic energy before themicrobubble therapeutic compound is expelled from the catheter and isdelivered to the treatment site.

In one embodiment, a microbubble therapeutic compound is infusedintra-arterially or intravenously to the treatment site before theultrasound radiating members are activated. Therefore, once theultrasound radiating members begin to generate ultrasonic energy, themicrobubble therapeutic compound is already at the treatment site. Insuch embodiments, the microbubble therapeutic compound is deliveredusing the same catheter that is used to the deliver the ultrasonicenergy. In a modified embodiment, the microbubble therapeutic compoundis delivered using a different catheter than that used to deliver theultrasonic energy, and delivery of the microbubble therapeutic compoundto the treatment site is optionally via the general vascularcirculation.

In an embodiment that is particularly advantageous for use with anultrasonic catheter having a cylindrical ultrasound radiating member,such as illustrated in FIGS. 12A and 12B, an insulating chamber is usedto reduce the amount of ultrasonic energy that is delivered into thecatheter fluid delivery lumen. Specifically, an insulating chamber ispositioned between the ultrasound radiating member and the deliverylumen. In such embodiments, the insulating chamber is filled with amaterial that does not efficiently transmit ultrasonic energy, therebyreducing the amount of ultrasonic energy reaching the fluid deliverylumen. Exemplary materials that can be put into the insulating chamberinclude, but are not limited to, air, nitrogen and oxygen. In a modifiedembodiment, an evacuated chamber is used.

FIG. 13 illustrates an exemplary embodiment of an ultrasound catheterhaving an ultrasound radiating member 320 separated from a deliverylumen 338 by an insulating chamber 330. The ultrasound radiating member320 is offset from the delivery lumen 338 using spacers 316 and supportmembers 318. Other configurations can be used in other embodiments.Additional information on using chambers to spatially direct ultrasonicenergy can be found in U.S. Pat. Nos. 6,582,392 and 6,676,626, theentire disclosure of which is incorporated herein by reference.

In a modified embodiment, the microbubble therapeutic compound isdelivered from an ultrasonic catheter intermittently with ultrasonicenergy. For example, in one such embodiment, during a first treatmentphase, the microbubble therapeutic compound is delivered withoutultrasonic energy. Then, during a second treatment phase, delivery ofthe microbubble therapeutic compound is paused and ultrasonic energy isdelivered to the treatment site. Optionally, the first and secondtreatment phases are alternately repeated several times. In oneembodiment, the duration of the first and second phases are each on theorder of approximately a few minutes. This configuration reduces theamount of cavitation occurring within the fluid delivery lumen of theultrasonic catheter. In other embodiments, the therapeutic compounddelivered to the treatment site is alternated between a therapeuticcompound that contains microbubbles and a therapeutic compound that doesnot contain microbubbles. In such embodiments, the phases withultrasonic energy correspond to the periods during which the therapeuticcompound that does not contain microbubbles is applied.

In one embodiment, the microbubble therapeutic compound is injecteddirectly into a vascular obstruction—such as a clot—at the treatmentsite. A schematic illustration of this embodiment is provided in FIG.14. Specifically, FIG. 14 illustrates a catheter 400 positioned withinan occlusion 410 at a treatment site within a patient's vasculature 420.A microbubble therapeutic compound 430 has been infused into theocclusion 410 from the catheter 400. Once the microbubble therapeuticcompound has been sufficiently infused, one or more ultrasound radiatingmembers 440 mounted within the catheter 400 can be energized, therebydelivering ultrasonic energy to the infused microbubble therapeuticcompound 430. The catheter 400 is optionally repositioned to directadditional ultrasonic energy into the infused microbubble therapeuticcompound 430. This technique allows microbubbles to be suspended withinthe obstruction. In such embodiments, ultrasonic energy is applied tothe obstruction, thereby causing mechanical agitation of themicrobubbles. The mechanical agitation of the microbubbles is effectivein mechanically breaking up clot material.

SCOPE OF THE INVENTION

While the foregoing detailed description discloses several embodimentsof the present invention, it should be understood that this disclosureis illustrative only and is not limiting of the present invention. Itshould be appreciated that the specific configurations and operationsdisclosed can differ from those described above, and that the methodsdescribed herein can be used in contexts other than treatment ofvascular occlusions.

1. A method of treating a vascular occlusion located at a treatment sitewithin a patient's vasculature, the method comprising: positioning anultrasound catheter at the treatment site; delivering a microbubbletherapeutic compound from the ultrasound catheter to the vascularocclusion during a first treatment phase; and pausing the delivery ofthe microbubble therapeutic compound and delivering ultrasonic energyfrom the ultrasound catheter to the vascular occlusion during a secondtreatment phase while the delivery of microbubble therapeutic compoundremains paused.
 2. The method of claim 1, further comprising measuring atemperature at the treatment site during the second treatment phase,wherein a duration of the second treatment phase is at least partiallydependent on the measured temperature.
 3. The method of claim 1, whereinthe first treatment phase has a duration between approximately oneminute and approximately three minutes.
 4. The method of claim 1,wherein the first treatment phase and the second treatment phase areapproximately the same duration.
 5. The method of claim 1, wherein thefirst treatment phase is longer than the second treatment phase.
 6. Themethod of claim 1, wherein the first treatment phase is shorter than thesecond treatment phase.
 7. The method of claim 1, further comprisingrepositioning the catheter after the first treatment phase and beforethe second treatment phase.
 8. The method of claim 1, wherein the firstand second treatment phases are alternately repeated a plurality oftimes.
 9. The method of claim 1, wherein the microbubble therapeuticcompound is infused from a catheter fluid delivery port positionedwithin the occlusion.
 10. The method of claim 1, wherein the microbubbletherapeutic compound is infused from a catheter fluid delivery portpositioned external to the occlusion.
 11. The method of claim 1, whereinthe microbubble therapeutic compound includes between approximately4×10⁶ and approximately 4×10⁸ microbubbles per milliliter.
 12. Themethod of claim 1, wherein the microbubble therapeutic compound includesmicrobubbles having a diameter of between approximately 0.1 μm andapproximately 100 μm.
 13. A method of treating a vascular occlusionlocated at a treatment site within a patient's vasculature, the methodcomprising: passing an ultrasound catheter through the patient'svasculature to the treatment site, wherein the ultrasound catheterincludes at least one fluid delivery port; positioning the ultrasoundcatheter at the treatment site such that the at least one fluid deliveryport is positioned within the occlusion; infusing a microbubbletherapeutic compound from the ultrasound catheter into an internalportion of the occlusion; pausing delivery of the microbubbletherapeutic compound from the ultrasound catheter after a first quantityhas been infused into the occlusion; delivering ultrasonic energy fromthe ultrasound catheter into the infused microbubble therapeuticcompound; repositioning the ultrasound catheter at the treatment site;and infusing a second quantity of microbubble therapeutic compound fromthe ultrasound catheter to the treatment site after the ultrasonicenergy is delivered to the treatment site.
 14. The method of claim 13,wherein the ultrasonic energy is delivered for between about one minuteand about three minutes.
 15. The method of claim 13, wherein themicrobubble therapeutic compound is delivered to the treatment site fora period of time that is approximately equal to a period of time duringwhich ultrasonic energy is delivered to the treatment site.
 16. Themethod of claim 13, further comprising measuring a temperature at thetreatment site, wherein the quantity of ultrasonic energy delivered intothe infused microbubble therapeutic compound is at least partiallydependent on the measured temperature.
 17. The method of claim 13,wherein the microbubble therapeutic compound includes betweenapproximately 4×10⁶ and approximately 4×10⁸ microbubbles per milliliter.18. The method of claim 13, wherein the microbubble therapeutic compoundincludes microbubbles having a diameter of between approximately 0.1 μmand approximately 100 μm21.
 19. The method of claim 13, wherein theultrasound catheter includes a plurality of ultrasound radiatingmembers.
 20. The method of claim 13, wherein the ultrasound radiatingmember comprises an ultrasound radiating member having a hollow innercore, and wherein the microbubble therapeutic compound is passed throughthe hollow inner core before being infused at the treatment site.
 21. Anultrasound catheter system comprising: an elongate tubular body havingan ultrasound radiating member and a fluid delivery lumen positionedtherein; a fluid reservoir that is hydraulically coupled to a proximalportion of the fluid delivery lumen, the fluid delivery reservoircontaining a microbubble therapeutic compound; an infusion pumpconfigured to pump the microbubble therapeutic compound from the fluidreservoir into the fluid delivery lumen; and control circuitryconfigured to send electrical activation power to the infusion pump andto the ultrasound radiating member, wherein the control circuitry isconfigured such that the infusion pump and the ultrasound radiatingmember are not activated simultaneously.
 22. The ultrasound cathetersystem of claim 21, further comprising a temperature sensor, wherein thecontrol circuitry sends electrical activation power to one of theinfusion pump and the ultrasound radiating member based on a temperaturesignal received from the temperature sensor.
 23. The ultrasound cathetersystem of claim 21, wherein a plurality of ultrasound radiating membersare positioned within the elongate tubular body.
 24. The ultrasoundcatheter system of claim 21, wherein a plurality of fluid deliverylumens are positioned within the elongate tubular body.
 25. Theultrasound catheter system of claim 21, wherein the tubular body has anouter diameter between about 2 French and about 5 French.